Pancreatic adenocarcinoma has a dismal 5-year survival of <5%. The only potential curative treatment is resection, but this is achieved in <20% of patients and most still die due to micrometastases or residual disease. Patients with unresectable disease receive palliative chemotherapy with a median survival of less than 11 months. This application proposes a multi-pronged approach with an aggressive chemoradiation regimen combined with a viral immuno-oncology product to attack residual and metastatic disease. The goal is to increase the resection rate and 2-year survival without further compromising quality of life. The project builds on a completed Phase 1a trial with Gene Mediated Cytotoxic Immunotherapy (GMCI) combined with chemoradiation and surgery that established a safe dose level and demonstrated immune stimulation in pancreatic cancer. GMCI generates a polyvalent anti-tumor immune response through local delivery of aglatimagene besadenovec (AdV-tk) plus prodrug and has demonstrated synergy with standard of care (SOC) in multiple tumor types. In preclinical studies, the CD8 T cell dependent systemic effect is potentiated by radiation, chemotherapy and surgery, which debulk and decrease immune-inhibitory factors elicited by tumors. GMCI significantly improved survival in a recent Phase 2 study in combination with chemoradiation in malignant glioma patients that had received total resection. A neoadjuvant regimen using modified FOLFIRINOX (mFX) followed by gemcitabine/radiation (GR) was piloted by the investigators at OSU in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). The regimen showed equivalent efficacy with less toxicity than standard FOLFIRINOX and led to more patients becoming resectable. Components of the regimen have been shown to suppress immune inhibitory factors elicited by tumors including myeloid derived suppressor cells (MDSC), regulatory T cells (Treg) and inhibitory cytokines. These data support the rationale for combining GMCI with mFX+ GR+ surgical resection. This Fast-Track application proposes a Ph-1b/2 clinical trial in BRPC and LAPC. The clinical protocol has received all the necessary regulatory approvals and is ready to launch. The protocol includes a single arm Phase Ib stage to establish the feasibility of the treatment plan (Phase I segment of the Fast-track grant) followed by a randomized Phase 2 stage of the trial (Phase II grant segment). Immune biomarkers including effector T cells, Tregs, MDSCs and cytokines will be measured before and after each treatment phase and compared between the control and test arm to better understand the mFX-+GR and GMCI immune effects in this patient population. This will be the first study of an immunotherapy combined with mFX+GR and the first randomized clinical study of GMCI for PanCa. The goal is to obtain the necessary data to support a decision for or against a definitive efficacy study that may improve the outcomes for patients with this devastating disease. The transition from Phase Ib to Phase II is preplanned in the protocol as a measurable milestone and will benefit from continuity, thus the Fast-Track submission.